Recent Advances in the Stereocontrolled Synthesis of Bi- and Tricyclic-β-Lactams with Non-Classical Structure

Benito      Alcaide; Pedro      Almendros

Abstract

β-Lactams (2-azetidinones) are one crucial structural element of the natural products with antibiotic properties. Since the introduction of penicillin into therapy, bacteria have developed an incredible and growing resistance to β-lactam antibiotics, essentially due to the hydrolytic ability of extremely active β-lactamases. The resistance of bacteria to the classical β-lactam antibiotics like penicillin and cephalosporin can be overcome, e.g., by using novel β-lactam moieties in drugs which show much higher stability towards these resistance bacteria. Furthermore, the recent discoveries of some azetidine-2-ones which display a broad range of enzyme-inhibitory activity justify a renewed interest in these compounds. Besides their significance as bioactive agents, the importance of β-lactams as synthetic intermediates have been widely recognized in organic synthesis. The 2-azetidinone skeleton has been extensively used as a template on which to build the carbo(hetero)cyclic stru cture fused to the four-membered ring, using the chirality and functionalization of the β-lactam ring as a stereocontrolling element. The present review will draw special attention to radical reactions, cycloaddition reactions (Diels-Alder, [2 + 2] cycloaddition reaction, and 1,3-dipolar cycloaddition), and transition metal-catalyzed reactions (Pauson-Khand reaction, ring closing metathesis and Pd-catalyzed cyclizations) as useful methods for the preparation of bi- and tricyclic-β-lactams with non-classical structure.

Keywords: penicil lins, cephalosporins, amoxicillin, trinems, reverse-cope elimination, cycloaddition reactions, dipolar cycloaddition reactions, diels-alder reaction